Compositions and methods for treating multiple sclerosis

ABSTRACT

Provided are compositions and methods for treating multiple sclerosis (MS). One embodiment of the disclosed method entails orally administering to a MS patient a first amount of aspirin and a second amount of fumaric acid or an ester or a salt thereof. In some embodiments, the aspirin is administered at from about 80 mg to about 500 mg per day and the fumaric acid or ester or salt thereof is administered at about 360 mg per day.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/922,729 filed Mar. 15, 2018, which claims the benefit under 35 U.S.C.§ 119(e) of U.S. Provisional Application Ser. No. 62/473,080 filed Mar.17, 2017, and Provisional Application Ser. No. 62/594,493, filed Dec. 4,2017, the contents of which are incorporated by reference in itsentirety into the present disclosure.

BACKGROUND

Multiple sclerosis (MS) is the most common autoimmune disorder affectingthe central nervous system. In 2013, about 2.3 million people wereaffected globally with rates varying widely in different regions andamong different populations. About 20,000 people died from MS in 2013,up from 12,000 in 1990. The disease usually begins between the ages of20 and 50 and is twice as common in women as in men.

Multiple sclerosis was first described in 1868 by Jean-Martin Charcot.The name multiple sclerosis refers to the numerous scars that develop onthe white matter of the brain and spinal cord. MS is a demyelinatingdisease in which the insulating covers of nerve cells in the brain andspinal cord are damaged. This damage disrupts the ability of parts ofthe nervous system to communicate, resulting in a range of signs andsymptoms, including physical, mental, and sometimes psychiatricproblems. Specific symptoms can include double vision, blindness in oneeye, muscle weakness, trouble with sensation, or trouble withcoordination. MS takes several forms, with new symptoms either occurringin isolated attacks (relapsing forms) or building up over time(progressive forms). Between attacks, symptoms may disappear completely;however, permanent neurological problems often remain, especially as thedisease advances.

While the cause is not clear, the underlying mechanism is thought to beeither destruction by the immune system or failure of themyelin-producing cells. Proposed causes for this include genetics andenvironmental factors such as being triggered by a viral infection. MSis usually diagnosed based on the presenting signs and symptoms and theresults of supporting medical tests.

There is no known cure for multiple sclerosis. Treatments attempt toimprove function after an attack and prevent new attacks. Medicationsused to treat MS, while modestly effective, can have side effects and bepoorly tolerated. Physical therapy can help with a patient's ability tofunction.

It has been shown that dimethyl fumarate (DMF) and its metabolite,monomethyl fumarate (MMF), are effective treatments forrelapse-remitting multiple sclerosis (RMMS). Both DMF and MMF activatethe nuclear-factor-E2-related factor-2 (Nrf2) transcriptional pathway,which induces anti-inflammatory and neuroprotective modalities in RMMSpatients. About 30% to 40% of treated individuals, however, suffer fromcutaneous flush which is associated with both DMF and MMF. Such adverseeffects, therefore, limit the use of DMF and MMF in treating MS.

SUMMARY

The present disclosure provides treatment regimens for diseases that canbe suitably treated with fumaric acid of its ester or salt, such asdimethyl fumarate (DMF), monomethyl fumarate (MMF), or the combinationthereof. Examples of such diseases include multiple sclerosis (MS),psoriasis, necrobiosis lipoidica, granuloma annulare, sarcoidosis,granulomatous and inflammatory skin disorders, lichen planus pityriasisrubra pilaris, chronic discoid lupus erythematosus, necrobiosislipoidica, cheilitis granulomatosa, annular elastotic giant cellgranuloma, malign melanoma, lupus erythematosus, aplopecia areata,hidradenitis suppurativa, other granulomatous and inflammatory skindisorders, other inflammatory disorders such as colitis, DNA damage intumor, gastrointestinal ulceration, collagen type II degradation, andother immune modulated diseases. In some embodiments, the treatmentmethods enable the effective use of a daily dose of fumaric acid or anester or salt thereof that is lower than their recommended use (e.g.,480 mg per day), without compromise of the treatment outcome.

It is discovered surprisingly that the methods and pharmaceuticalcompositions described herein may increase the bioavailability of thefumaric acid or an ester or salt thereof (e.g., dimethyl fumarate) suchthat a significantly lower dose can be administered (e.g., 420, 400 or360 mg per day), without compromise of the treatment outcome. Inaddition, in some embodiments, the treatment methods allow a patient totolerate a higher dose of fumaric acid or an ester or salt thereof,which higher dose may be required given the condition and otherrequirements of the patient.

In one embodiment, provided is a method of treating multiple sclerosis(MS) in a human patient in need thereof, comprising orally administeringto the patient aspirin and fumaric acid or an ester or a salt thereof,wherein the aspirin is administered at from about 150 mg to about 650 mg(or from about 300 mg to about 500 mg) per day and the fumaric acid orester or salt thereof is administered at about 300 mg to about 450 mgper day (or from about 340 mg to about 380 mg per day). The aspirin andthe fumaric acid or ester or a salt thereof can be administeredseparately or together, concurrently or sequentially.

In some embodiments, the aspirin is formulated to dissolve in an oralcavity of a subject. In some embodiments, the fumaric acid or ester orsalt thereof is formulated for dissolving in stomach, intestines, orfurther distal in the gastrointestinal tract of the subject.

Also provided, in one embodiment, is a method of treating multiplesclerosis (MS) in a human patient in need thereof, comprising orallyadministering to the patient one or more tablets each comprising a firstportion comprising a first amount of aspirin and a second portioncomprising a second amount of fumaric acid or an ester or a saltthereof, wherein the first portion is formulated to dissolve in an oralcavity of a subject, wherein the second portion is formulated fordissolving in stomach, intestines, or further distal in thegastrointestinal tract of the subject, and wherein the aspirin isadministered at from about 150 (or 160, 170, 180, 190, 200, 210, 220,230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360,370, 380, 390 or 400) mg to about 650 (or 410, 420, 430, 440, 450, 460,470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600,610, 620, 630, or 640) mg per day and the fumaric acid or ester or saltthereof is administered at about 300 (or 300, 310, 320, 330, 340, 350,or 360) mg to about 450 (or 360, 370, 380, 390, 400, 410, 420, 430, 440,or 450) mg per day.

In some embodiments, the patient suffers from relapse-remitting MS(RRMS). In some embodiments, the patient has a history of non-compliancewith a medication due to cutaneous flush or a gastrointestinal sideeffect.

In some embodiments, the second amount of the fumaric acid or ester orsalt thereof is about 180 mg. In some embodiments, the first amount ofaspirin is from about 80 mg to about 250 mg. In some embodiments, thesecond portion further comprises a third amount of aspirin. In someembodiments, the first amount of aspirin and the second amount ofaspirin each is from about 40 mg to about 120 mg. In some embodiments,the second portion is enclosed in an enteric coating.

In some embodiments, the ester is dimethyl fumarate, monomethyl fumarateor combination thereof.

Pharmaceutical compositions are also provided. In some embodiments, thepharmaceutical composition is a fixed dose combination comprisingaspirin and a fumaric acid or an ester or a salt thereof. In someembodiments, the pharmaceutical composition is a fixed dose combinationcomprising aspirin and dimethyl fumarate, optionally in combination withan additional fumaric acid or an ester or a salt thereof.

In some embodiments, the pharmaceutical composition comprises about 40(or 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, or190) mg to about 250 (or 210, 220, 230, or 240) mg of aspirin and about150 (or 160, 165, 170, 175, 180, or 185) mg to about 190 (or 180, 185,195, 200, 210, 220, 225, or 230) mg of fumaric acid or an ester or asalt thereof. In some embodiments, the pharmaceutical compositioncomprises about 300 (or 310, 320, 330, 340, 350, 360, 370, 380, 390 or400) mg to about 500 (or 410, 420, 430, 440, 450, 460, 470, 480, or 490)mg of aspirin and about 340 (or 300, 310, 320, 330, 350, or 360) mg toabout 380 (or 360, 370, 380, 390, 400, 410, 420, 430, 440, or 450) mg offumaric acid or an ester or a salt thereof.

In some embodiments, the pharmaceutical compositions described hereinare formulated as a tablet. In some embodiments, the pharmaceuticalcompositions described herein are formulated as a capsule comprising theaspirin and a fumaric acid or an ester or a salt thereof. In someembodiments, the pharmaceutical compositions described herein areformulated as a capsule comprising the aspirin and a fumaric acid or anester or a salt thereof, wherein the aspirin and fumaric acid or anester or a salt thereof are each formulated as a microsphere. In someembodiments, the aspirin is present in a first portion formulated todissolve in an oral cavity of a subject, and the fumaric acid or esteror salt thereof is present in a second portion formulated for dissolvingin stomach, intestines, or further distal in the gastrointestinal tractof the subject.

In some embodiments, the aspirin is present in a first portionformulated to dissolve in an oral cavity of a subject, and a secondportion formulated for dissolving in stomach, intestines, or furtherdistal in the gastrointestinal tract of the subject. In someembodiments, the pharmaceutical compositions described herein areformulated as a capsule comprising the aspirin and a fumaric acid or anester or a salt thereof, wherein the aspirin and fumaric acid or anester or a salt thereof are each formulated as a microsphere containedwithin a capsule shell, and a second portion of aspirin is present as acoating on the capsule shell and is formulated to dissolve in an oralcavity of a subject. By administering this particular dosage form, it iscontemplated that the effective dose of DMF can be reduced, thusreducing and/or relieving one or more side effects of DMF.

In one embodiment, provided is a method of treating multiple sclerosis(MS) in a human patient in need thereof, comprising orally administeringto the patient aspirin and fumaric acid or an ester or a salt thereof,wherein the aspirin is administered at from about 300 mg to about 500 mgper day and the fumaric acid or ester or salt thereof is administered atabout 580 mg to about 620 mg per day. In some embodiments, the aspirinis formulated to dissolve in an oral cavity of a subject. In someembodiments, the fumaric acid or ester or salt thereof is formulated fordissolving in stomach, intestines, or further distal in thegastrointestinal tract of the subject. In some embodiments, the aspirinand the fumaric acid or ester or salt thereof are administeredconcurrently.

Also provided, in one embodiment, is a method of treating multiplesclerosis (MS) in a human patient in need thereof, comprising orallyadministering to the patient one or more tablets each comprising a firstportion comprising a first amount of aspirin and a second portioncomprising a second amount of fumaric acid or an ester or a saltthereof, wherein the first portion is formulated to dissolve in an oralcavity of a subject, wherein the second portion is formulated fordissolving in stomach, intestines, or further distal in thegastrointestinal tract of the subject, and wherein the aspirin isadministered at from about 150 mg to about 650 mg per day and thefumaric acid or ester or salt thereof is administered at about 570 mg toabout 630 mg per day, or about 300 to about 450 mg per day, or about 300to about 400 mg per day, or about 350 to about 400 mg per day, or about360 mg per day.

In some embodiments, the patient suffers from relapse-remitting MS(RRMS). In some embodiments, the patient suffers from secondaryprogressive multiple sclerosis (SPMS).

Also provided, in one embodiment, is a method of treating psoriasis in ahuman patient in need thereof, comprising orally administering to thepatient one or more tablets each comprising a first portion comprising afirst amount of aspirin and a second portion comprising a second amountof fumaric acid or an ester or a salt thereof, wherein the first portionis formulated to dissolve in an oral cavity of a subject, wherein thesecond portion is formulated for dissolving in stomach, intestines, orfurther distal in the gastrointestinal tract of the subject, and whereinthe aspirin is administered at from about 150 mg to about 650 mg per dayand the fumaric acid or ester or salt thereof is administered at about570 mg to about 630 mg per day, or about 300 to about 450 mg per day, orabout 300 to about 400 mg per day, or about 350 to about 400 mg per day,or about 360 mg per day.

In addition to multiple sclerosis and psoriasis, fumaric acid or esteror salt thereof can also be used for treating other diseases andconditions such as motor neuron disease, neurodegenerative diseases,autoimmune diseases, inflammatory diseases, sepsis, and skin diseases orconditions.

A motor neuron disease a neurological condition that selectively affectsmotor neurons. Examples include amyotrophic lateral sclerosis (ALS),hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS),progressive muscular atrophy (PMA), progressive bulbar palsy (PBP) andpseudobulbar palsy.

Neurodegenerative diseases are results of progressive loss of structureor function of neurons, including death of neurons. Examples includeamyotrophic lateral sclerosis, Parkinson's, Alzheimer's, andHuntington's, which occur as a result of neurodegenerative processes.

Non-limiting examples of autoimmune or inflammatory disease includeParkinson's disease, arthritis, rheumatoid arthritis, multiplesclerosis, psoriasis, psoriatic arthritis, Crohn's disease, inflammatorybowel disease, ulcerative colitis, lupus, systemic lupus erythematous,juvenile rheumatoid arthritis, juvenile idiopathic arthritis, Grave'sdisease, Hashimoto's thyroiditis, Addison's disease, celiac disease,dermatomyositis, multiple sclerosis, myasthenia gravis, perniciousanemia, Sjogren syndrome, type I diabetes, vasculitis, uveitis,atherosclerosis and ankylosing spondylitis.

Skin diseases are various skin problems, from small red bumps on theskin to widespread rashes. Some skin conditions can be unsightly butharmless, while others may be contagious. Many skin conditions are alsoitchy or painful. The presently disclosed compositions and methods aresuitable for treating these diseases and the symptoms. Non-limitingexamples of symptoms include itch, swelling, redness, rash, flaky, scalyskin, blisters, oozing and bumps or growths.

In some embodiments, the second amount of the fumaric acid or ester orsalt thereof is about 300 mg. In some embodiments, the first amount ofaspirin is from about 80 mg to about 250 mg. In some embodiments, thesecond portion further comprises a third amount of aspirin. In someembodiments, the first amount of aspirin and the second amount ofaspirin each is from about 80 mg to about 120 mg. In some embodiments,the first portion further comprises a water-soluble sugar or sugarsubstitute. In some embodiments, the second portion is enclosed in anenteric coating. In some embodiments, the ester is dimethyl fumarate,monomethyl fumarate or combination thereof. In some embodiments, themonomethyl fumarate is hydrogen monomethyl fumarate or a salt thereof(e.g., Na⁺, K⁺, Ca²⁺, Zn²⁺, Mg²⁺, Fe²⁺). In some embodiments, themonomethyl fumarate is hydrogen monomethyl fumarate.

Pharmaceutical compositions are also provided, for example, suitable foronce daily, twice daily, or three times daily administration. In oneembodiment, the composition comprises about 100 (or 110, 120, 130, 140,150, 160, 170, 180, 190, or 200) mg to about 250 (or 200, 210, 220, 230,or 240) mg of aspirin and about 170 (or 175, 180, 185, or 190) mg toabout 220 (or 185, 190, 195, 200, 205, 210, or 215) mg of fumaric acidor an ester or a salt thereof. In one embodiment, the compositioncomprises about 150 (or 160, 170, 180, or 190) mg to about 250 (or 210,220, 230, or 240) mg of aspirin and about 285 (or 270, 270, 280, 290,295, or 300) mg to about 315 (or 300, 305, 310, 320, or 325) mg offumaric acid or an ester or a salt thereof. In one embodiment, thecomposition comprises about 300 (or 310, 320, 330, 340, 350, 360, 370,380, 390 or 400) mg to about 500 (or 410, 420, 430, 440, 450, 460, 470,480, or 490) mg of aspirin and about 570 (or 560, 565, 575, 580, 590 or595) mg to about 630 (or 605, 610, 515, 620, 625, 635, or 640) mg offumaric acid or an ester or a salt thereof. In one embodiment, thecomposition comprises about 40 (or 20, 30, 40, 50, 60, 70, 80, 90, 100or 120) mg to about 500 (or 410, 420, 430, 440, 450, 460, 470, 480, or490) mg of aspirin and about 120 (or 130, 140, 150, 160, 170, 180, 190,200, 210 or 220) mg to about 240 (or or 210, 220, 230, or 240) mg offumaric acid or an ester or a salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an example of the scale that was used to rate the assessmentof Question 1 in Example 4.

FIG. 2 is an example of the scale that was used to rate the assessmentof Questions 2 and 3 in Example 4.

DETAILED DESCRIPTION

The following description sets forth exemplary embodiments of thepresent technology. It should be recognized, however, that suchdescription is not intended as a limitation on the scope of the presentdisclosure but is instead provided as a description of exemplaryembodiments.

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

“Relapse-remitting multiple sclerosis,” or RRMS, is a type of MS ofwhich symptoms can appear suddenly and be severe and can then go quietfor months or years. Between flare-ups, the disease tends not toprogress or progresses relatively slowly, and symptoms may disappear.

“Secondary-progressive multiple sclerosis,” or SPMS, is a MS conditionin which the disease tends to progress steadily. This can happen with orwithout relapses. Many patients with RRMS may transition to SPMS at somepoint in the course of their disease.

“Fumaric acid” is the chemical compound with the formula HO₂CCH═CHCO₂H.The “salts and esters” of fumaric acid are known as fumarates, andinclude any ester (e.g., mono ester hydrogen fumarate or salt thereof ordiester of fumaric acid), such as dimethyl fumarate (DMF) and monomethylfumarate (MMF). The fumaric acid can comprise a mixture of DMF, alsothree monoethyl hydrogen fumarates or salt thereof (calcium, magnesium,and zinc salts) (e.g., Fumaderm®). The fumaric acid can comprise ALKS8700 (“a MMF molecule” which is a prodrug to MMF).

Dimethyl fumarate (DMF) is the dimethyl ester of fumaric acid, having achemical name of dimethyl (E)-butenedioate. DMF and its metabolite,monomethyl fumarate (MMF), were initially recognized as effectivehypoxic cell radiosensitizers. They are also used as oral therapy forpsoriasis. Other diseases, such as necrobiosis lipoidica, granulomaannulare, and sarcoidosis may also be suitably treated with DMF and MMF.

In a non-medical setting, DMF is applied as a biocide to prevent growthsof mold during storage or transport in a humid climate. However, due toincidences of allergic reactions after skin contact the European Unionbanned DMF in consumer products since 1998, and since January 2009 theimport of products containing DMF was also banned. Medical use of DMFalso is known to come with associated side effects, such as progressivemultifocal leukoencephalopathy, which can be serious. Another sideeffect associated with the use of DMF or MMF is the flushing, which hasbeen reported to cause non-compliance of patients.

A commercial form of DMF for treating MS is Tecfidera®. According to thedrug label, the starting dose for Tecfidera® is 120 mg twice a dayorally. After 7 days, the dose should be increased to the maintenancedose of 240 mg twice a day orally. Temporary dose reductions to 120 mgtwice a day may be considered for individuals who do not tolerate themaintenance dose. Higher doses of Tecfidera® are not recommended.

It is a surprising and unexpected discovery of the instant inventor thatadministration of both aspirin and fumaric acid or its ester or saltsuch as DMF and MMF achieves increased treatment efficacy and reducedside effects as compared to the fumarate alone. Such a dualadministration, therefore, makes it possible to use a lower dose (e.g.,420, 400 or 360 mg per day) of fumaric acid of the ester or saltthereof, as compared to the conventional commercial dose (e.g., 480 mgper day), to achieve the same efficacy as the conventional dose wouldbut with greatly reduced side effects.

The impact of aspirin on the bioavailability of DMF has been evaluatedpreviously and acknowledged by the US FDA. In Sheikh et al., Clin Ther.2013; 35:1582-94, for example, the authors observed that pretreatmentwith 325 mg aspirin for 4 days reduced flushing incidence and intensitybut did not affect gastrointestinal events or the pharmacokineticprofile of DMF (abstract). In other words, aspirin pretreatment did notchange the bioavailability of the DMF. Accordingly, the presentdiscovery that concomitant administration of aspirin increased thebioavailability of DMF by about 5% is necessarily surprising andunexpected.

Such a surprising and unexpected discovery that the dual administrationincreases the bioavailability of the fumarate (e.g., DMF) makes itpossible to use a lower dose (e.g., 420, 400 or 360 mg per day) whileachieving the same or substantially similar efficacy as compared to theconventional commercial dose (e.g., 480 mg per day), to achieve the sameefficacy as the conventional dose. On the other hand, this dualformulation allows administration of a higher dose (e.g., 600 mg perday) of fumaric acid of the ester or salt thereof so that patients whodesire such high doses can avoid or suffer reduced undesirable sideeffects such as flushing. The dual administration can be sequentialadministration or concurrent administration of two or more separatecompositions, or administration of a composition that includes two ormore different ingredients.

In some embodiments, a co-formulation is disclosed. In some aspects, theaspirin and fumaric acid of the ester or salt thereof are in separateportions in the co-formulation, such as a tablet. In some aspects, theseparate portions are formulated similarly and in other aspects, theaspirin portion is formulated in a dissolvable fashion (dissolvableportion) and the fumaric acid portion is formulated as a swallowablefashion (swallowable portion). In some aspects, the swallowable portionalso contains an amount of aspirin, which is shown to further enhancethe effect of the dissolvable aspirin in a synergistic fashion.

In some embodiments, a similarly structured co-formulation is disclosedthat includes aspirin and therapeutic agent having a niacin-mediatedflushing side effect. The term “therapeutic agent having aniacin-mediated flushing side effect,” as used herein, refers to a groupof drugs that activate the nicotinic acid receptor GPR109a, resulting influshing symptoms commonly observed for patients taking niacin.Sometimes, such agents are also referred to as “nicotinic acid receptoragonists” or “GPR109a agonists.” Non-limiting examples of suchtherapeutic agents include niacin, nicotyinyl alcohol, acipimox,acifran, newer GPR109a agonists, hydroxybutyrate, and fumarates (e.g.,dimethyl fumarate, mono-ethyl fumarate, diethyl fumarate).

Structure-activity studies have shown common structural features ofGPR109a agonists. Some of the GPR109a agonists have a carcoxyl group,like in niacin. Another group are anthranilic acid analogs. More of suchstructural elements are discussed in Boatman et al. J. Med. Chem. 2008;51(24):7653-62.

In some embodiments, aspirin can be substituted with a non-steroidalanti-inflammation drug (NSAID). Non-limiting examples of NSAIDs includeaspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen,indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin,piroxicam, salsalate, sulindac, and tolmetin.

A “dissolvable portion” as used herein refers to a portion of a drugform that is formulated to dissolve in an oral cavity of a subject. Adissolvable portion, in one embodiment, is pulverizable which can bedispersed in the oral cavity by masticating, sucking, dissolving orother common means, thereby releasing its active ingredient into theoral cavity where it enters the circulatory system by traversing thebuccal mucosa. Other embodiments of dissolvable portions are alsoprovided below in the present disclosure.

A “swallowable portion” is relative to the dissolvable portion and canbe harder than the dissolvable portion. Therefore, the swallowableportion is more readily swallowed by the subject and releases the activeingredient by dissolving it in stomach, intestines, or further distal inthe gastrointestinal (GI) tract of the subject.

The dissolvable portion and the swallowable portion, in someembodiments, are side by side in a tablet but with different physical orchemical properties. In some embodiments, the intraoral is placedoutside of the swallowable portion to form a bi-layer tablet.

In the context of the present disclosure, the use of the term hard orswallowable in reference to the dissolvable portion is used to connotethat the swallowable portion is not pulverized by the force and canwithstand the force of masticating or chewing that effectivelypulverizes the outer layer of the pharmaceutical composition of thepresent disclosure. In one embodiment, the swallowable portion ischew-resistant. Further, in referring to the swallowable portion asbeing ingestible, it is meant that the swallowable portion is capable ofbeing taken up and absorbed by one or more portions of thegastrointestinal tract, stomach, intestines or a further distal of thegastrointestinal tract. The swallowable portion of the combinationtablet may be conventionally covered with one or more layers of coatingsto permit a timed release of the active contained therein followingingestion by a subject. The present disclosure contemplates a releaseprofile of the ingested core particle of from 30 minutes to 24 hours.

In the context of the present disclosure, the term pulverizable oreasily pulverizable refers to a portion of a material that is ground ordispersed into small particles within the oral cavity by gentle pressuregenerated by chewing or masticating the layer to be ground. There is nointent to imply any particular size or fineness of the resultingparticles, as it is contemplated herein that it is only required thatthe pulverized material release a therapeutic agent within the oralcavity.

The term masticating or chewing, in the context of the presentdisclosure, is meant to signify that the pulverizing or grinding isbeing performed by a patient's or subject's teeth, or gums. A specificembodiment of the combination pill may cause the first bite(s) torupture or dislodge the outer layer thereby releasing it from thecentral core and can then be chewed. There is no intent to signify anyparticular degree of force required or generated by the masticatingteeth or gums. The requirement is that the force actually used toproduce the pulverized granules, particles, powder and the like, issufficient to disrupt the dissolvable portion of the present disclosurewhile leaving the swallowable portion intact.

The term sucking, dissolving or other common means, in the context ofthe present disclosure, is meant to signify that the intraoral orpulverizable portion can be absorbed in the oral cavity through use ofthe tongue, gums, cheeks, saliva and combinations thereof, over a periodof time. A specific embodiment of the combination pill causes theintraoral or pulverizable portion to dissolve in the oral cavity over aperiod of 5 minutes, while the combination pill is held in the oralcavity, through interaction with saliva. The requirement is thatinteraction with the tongue, gums, cheeks, saliva and combinationsthereof by sucking, dissolving or other common means, is sufficient todisrupt the outer layer of the pharmaceutical composition of the presentdisclosure while leaving the swallowable portion intact.

For the purpose of this description, the term intact does not requirethat the swallowable portion remain in one piece. Instead, it signifiesthat at least 50% of the swallowable portion is swallowed, butpreferably that 75% of the swallowable portion material is swallowed;even more preferably that approximately 75% to about 85% of theswallowable portion material is swallowed, and most preferably, fromabout 85% to about 95% of the swallowable portion material is swallowed,and most particularly, that greater than 95% of the swallowable portionmaterial is swallowed.

The buccal mucosa is meant to refer to the epithelium lining the oralcavity, including the sublingual region. The buccal mucosa furtherincludes the sub-epithelial tissue; i.e., the tissue and macromolecularlayers that accumulate underneath the epithelium. The sub-epithelialtissue includes, inter alia, connective tissue cells (fibroblasts,adipocytes, lymphocytes, and the like), extracellular matrix, basementmembrane, smooth muscle, and vascular elements, etc. The buccal mucosais a highly vascular tissue, and therefore a desirable route of entryinto the general circulation.

In one embodiment, the present disclosure provides a method of treatingmultiple sclerosis (MS) in a human patient in need thereof. In someembodiments, the disease or condition being treated is one or more ofpsoriasis, necrobiosis lipoidica, granuloma annulare, sarcoidosis,granulomatous and inflammatory skin disorders, lichen planus pityriasisrubra pilaris, chronic discoid lupus erythematosus, necrobiosislipoidica, cheilitis granulomatosa, annular elastotic giant cellgranuloma, malign melanoma, lupus erythematosus, aplopecia areata,hidradenitis suppurativa, other granulomatous and inflammatory skindisorders, other inflammatory disorders such as colitis, DNA damage intumor, gastrointestinal ulceration, collagen type II degradation, andother immune modulated diseases.

The method entails, in one embodiment, orally administering to thepatient a first amount of aspirin and a second amount of fumaric acid oran ester or a salt thereof. In some embodiments, the aspirin isadministered at from about 300 mg to about 500 mg per day and thefumaric acid or ester or salt thereof is administered at about 340 mg toabout 380 mg per day.

The method entails, in one embodiment, orally administering to thepatient one or more tablets each comprising a first portion comprising afirst amount of aspirin and a second portion comprising a second amountof fumaric acid or an ester or a salt thereof, wherein the first portionis formulated to dissolve in an oral cavity of a subject, wherein thesecond portion is formulated for dissolving in stomach, intestines, orfurther distal in the gastrointestinal tract of the subject, and whereinthe aspirin is administered at from about 300 mg to about 500 mg per dayand the fumaric acid or ester or salt thereof is administered at about340 mg to about 380 mg per day.

In some embodiments, the daily dose of the fumaric acid or ester or saltthereof is about 350 mg to about 370 mg, or about 355 mg to about 365mg, or about 360 mg.

In some aspects, the daily administration is twice daily, and eachadministration is with one or two tablets. In one aspect, the secondportion of each tablet, also referred to as the swallowable portion,contains about 170 mg to about 190 mg fumaric acid or an ester or saltthereof. In one aspect, the second portion of each tablet, also referredto as the swallowable portion, contains about 175 mg to about 185 mgfumaric acid or an ester or salt thereof. In one aspect, the secondportion of each tablet, also referred to as the swallowable portion,contains about 180 mg fumaric acid or an ester or salt thereof.

In one aspect, the first portion of each tablet, also referred to as thedissolvable portion, contains about 150 mg to about 250 mg aspirin, oralternatively about 175 mg to about 225 mg aspirin, or about 200 mgaspirin. In some embodiments, the first portion contains about 75 mg toabout 125 mg aspirin, or alternatively about 90 mg to about 110 mgaspirin, or about 100 mg aspirin, and meanwhile the second portionfurther contains about 75 mg to about 125 mg aspirin, or alternativelyabout 90 mg to about 110 mg aspirin, or about 100 mg aspirin, such thatthe total amount of aspirin in each tablet can still be about 150 mg toabout 250 mg.

In some embodiments, the patient suffers from relapse-remitting MS(RRMS), a relatively common form of MS. In some embodiments, the patienthas a history of non-compliance with a medication due to cutaneous flushor a gastrointestinal side effect. “Non-compliance” as used hereinrefers to a patient's failure, of at least one time, to take the DMF/MMFmedication due to complaint of flushing. In some embodiments, thepatient has suspended taking DMF/MMF for at least 1 week, 2 weeks, 1month, 2 months, 3 months, or 6 months.

In one embodiment, the present disclosure provides a method of treatingmultiple sclerosis (MS) in a human patient in need thereof.

In some embodiments, the disease or condition being treated is one ormore of psoriasis, necrobiosis lipoidica, granuloma annulare,sarcoidosis, granulomatous and inflammatory skin disorders, lichenplanus pityriasis rubra pilaris, chronic discoid lupus erythematosus,necrobiosis lipoidica, cheilitis granulomatosa, annular elastotic giantcell granuloma, malign melanoma, lupus erythematosus, aplopecia areata,hidradenitis suppurativa, other granulomatous and inflammatory skindisorders, other inflammatory disorders such as colitis, DNA damage intumor, gastrointestinal ulceration, collagen type II degradation, andother immune modulated diseases.

The method entails, in one embodiment, orally administering to thepatient a first amount of aspirin and a second amount of fumaric acid oran ester or a salt thereof. In some embodiments, the aspirin isadministered at from about 300 mg to about 500 mg per day and thefumaric acid or ester or salt thereof is administered at about 570 mg toabout 630 mg per day.

The method entails, in one embodiment, orally administering to thepatient one or more tablets each comprising a first portion comprising afirst amount of aspirin and a second portion comprising a second amountof fumaric acid or an ester or a salt thereof, wherein the first portionis formulated to dissolve in an oral cavity of a subject, wherein thesecond portion is formulated for dissolving in stomach, intestines, orfurther distal in the gastrointestinal tract of the subject, and whereinthe aspirin is administered at from about 300 mg to about 500 mg per dayand the fumaric acid or ester or salt thereof is administered at about570 (or 575, 580, 585, 590, or 595) mg to about 630 (or 605, 610, 615,620 or 625) mg per day.

In some embodiments, the daily dose of the fumaric acid or ester or saltthereof is about 590 mg to about 610 mg, or about 595 mg to about 605mg, or about 600 mg.

In some aspects, the daily administration is once, twice or three timesdaily, and each administration is with one or two tablets. In oneaspect, the second portion of each tablet, also referred to as theswallowable portion, contains about 290 mg to about 310 mg fumaric acidor an ester or salt thereof. In one aspect, the second portion of eachtablet, also referred to as the swallowable portion, contains about 295mg to about 305 mg fumaric acid or an ester or salt thereof. In oneaspect, the second portion of each tablet, also referred to as theswallowable portion, contains about 300 mg fumaric acid or an ester orsalt thereof.

In one aspect, the first portion of each tablet, also referred to as thedissolvable portion, contains about 150 mg to about 250 mg aspirin, oralternatively about 175 mg to about 225 mg aspirin, or about 200 mgaspirin. In some embodiments, the first portion contains about 75 mg toabout 125 mg aspirin, or alternatively about 90 mg to about 110 mgaspirin, or about 100 mg aspirin, and meanwhile the second portionfurther contains about 75 mg to about 125 mg aspirin, or alternativelyabout 90 mg to about 110 mg aspirin, or about 100 mg aspirin, such thatthe total amount of aspirin in each tablet can still be about 150 mg toabout 250 mg.

In some embodiments, the patient has been treated with fumaric acid oran ester or salt thereof but the treatment is considered inadequate. Insome embodiments, the patient suffers from relapse-remitting MS (RRMS).In some embodiments, the patient suffers from secondary progressivemultiple sclerosis (SPMS).

Example Co-Formulations

Pharmaceutical formulations are provided, in some embodiments. Theformulations may include aspirin at a suitable dose and form and afumaric acid or an ester or a salt thereof at a suitable dose and form.In some embodiments, the formulation includes at last about 20, 30, 40,50, 60, 70, 80, 90, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145,150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215,220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285,290, 295, or 300 mg aspirin. In some embodiments, the formulationincludes not more than about 500, 490, 480, 470, 460, 450, 440, 430,420, 410, 400, 390, 380, 370, 360, 350, 340, 330, 325, 320, 315, 310,305, 300, 295, 290, 285, 280, 275, 260, 255, 250, 245, 240, 235, 230,225, 220, 215, 210, 205, 200, 190, 180, 170, 160, or 150 mg aspirin.

In some embodiments, the formulation includes at least about 80, 90,100, 120, 125, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200,205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270,275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340,345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410,415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480,485, 490, 495, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, or 600mg of a fumaric acid or an ester or a salt thereof. In some embodiments,the formulation include not more than about 600, 590, 580, 570, 560, 55,540, 530, 520, 510, 500, 490, 480, 470, 460, 450, 440, 430, 420, 410,400, 390, 380, 370, 360, 350, 340, 330, 325, 320, 315, 310, 305, 300,295, 290, 285, 280, 275, 260, 255, 250, 245, 240, 235, 230, 225, 220,215, 210, 205, 200, 195, 190, 185, 180, 175, 170, 165, 160, 155, or 150mg of a fumaric acid or an ester or a salt thereof.

In some embodiments, the fumaric acid or an ester or a salt thereof isdimethyl fumarate, optionally in combination with an additional fumaricacid or an ester or a salt thereof. In some embodiments, the additionalfumaric acid or an ester or a salt thereof is monomethyl fumarate or asalt thereof (e.g., Na⁺, K⁺, Ca²⁺, Zn²⁺, Mg²⁺, Fe²⁺). In someembodiments, the monomethyl fumarate is hydrogen monomethyl fumarate. Insome embodiments, the pharmaceutical composition consists essentially ofan effective amount of aspirin and an effective amount of dimethylfumarate.

In some embodiments, the pharmaceutical composition comprises from about80 mg to about 380 mg of the fumaric acid or ester or salt thereof. Insome embodiments, the pharmaceutical composition comprises from about 80mg to about 380 mg of the dimethyl fumarate. In some embodiments, thepharmaceutical composition comprises from about 30 mg to about 500 mg ofaspirin. In some embodiments, the pharmaceutical composition comprisesfrom about 150 mg to about 500 mg of aspirin. In some embodiments, thepharmaceutical composition comprises from about 30 mg to about 500 mg ofaspirin and from about 80 mg to about 380 mg of a fumaric acid or anester or a salt thereof. In some embodiments, the pharmaceuticalcomposition comprises from about 150 mg to about 500 mg of aspirin andfrom about 80 mg to about 380 mg of a fumaric acid or an ester or a saltthereof.

In some embodiments, the pharmaceutical compositions described hereinare formulated as a capsule comprising aspirin and a fumaric acid or anester or a salt thereof, wherein the aspirin and fumaric acid or anester or a salt thereof are each formulated as a microsphere containedwithin a capsule shell, and a second portion of aspirin is present as acoating on the capsule shell and is formulated to dissolve in an oralcavity of a subject.

In some embodiments, the pharmaceutical composition, or dosage form,provided herein comprises aspirin and a fumaric acid or an ester or asalt thereof, wherein the aspirin and fumaric acid or an ester or a saltthereof are each individually formulated as enterically coatedmicrospheres which are contained within a capsule shell. In someembodiments, the capsule may also be coated with a second portion ofaspirin formulated to dissolve in an oral cavity of a subject. In someembodiments, the total dose of aspirin of the capsule (i.e., thecombined amount present within the capsule in combination with theaspirin present as a coating on the capsule shell) is about 20 mg toabout 500 mg, or about 20 mg to about 325 mg, or about 20 mg, or about25 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg,or about 70 mg, or about 75 mg, or about 80 mg, or about 90 mg, or about100 mg, or about 110 mg, or about 120 mg, or about 130 mg, or about 140mg, or about 150 mg, or about 160 mg, or about 170 mg, or about 180 mg,or about 190 mg, or about 200 mg, or about 210 mg, or about 220 mg, orabout 230 mg, or about 240 mg, or about 250 mg, or about 260 mg, orabout 270 mg, or about 280 mg, or about 290 mg, or about 300 mg, orabout 310 mg, or about 315 mg, or about 320 mg, or about 325 mg.

In some embodiments, the total dose of aspirin of the capsule is presentin about a 1:1 ratio between the aspirin microspheres within the capsuleand the aspirin present as a coating on the capsule shell. In someembodiments, the dose of aspirin present as microspheres within thecapsule is about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg,or about 60 mg, or about 70 mg, or about 75 mg, or about 80 mg. In someembodiments, the dose of aspirin present as a coating on the capsuleshell is about 20 mg, or about 25 mg, or about 30 mg, or about 40 mg, orabout 50 mg, or about 60 mg, or about 70 mg, or about 75 mg, or about 80mg.

The microspheres described herein may also include non-sphericalmicroparticles, such as oblong or cylindrical microparticles.

In some embodiments, the microspheres described herein have an averageparticle size of less than about 7 mm, or less than about 6 mm, or lessthan about 5 mm, or less than about 4 mm, or less than about 3 mm, orless than about 2 mm, or less than about 1.7 mm, or less than about 1.6mm, or less than about 1.5 mm, or less than about 1.4 mm, or less thanabout 1.3 mm, or less than about 1.2 mm, or less than about 1.1 mm, orless than about 1.0 mm, or less than about 900 μm, or less than about850 μm, or less than about 800 μm, or less than about 750 μm, or lessthan about 700 μm, or less than about 650 μm, or less than about 600 μm,or less than about 550 μm, or less than about 500 μm, or less than about450 μm, or less than about 300 μm. In some embodiments, the particlesize ranges from about 900 μm to about 2,000 μm, or from about 850 μm toabout 1.7 mm, or from about 1.0 mm to 1.5 mm.

In some embodiments, the microspheres comprise an enteric coating suchthat the API (aspirin or fumaric acid or an ester or a salt thereof(e.g., DMF)) is released in the gastrointestinal tract (e.g., the smallintestine). In some embodiments, the enteric coating on the microspheresis formulated or applied such that the aspirin is released in thegastrointestinal tract (e.g., the small intestine) at substantially thesame time as the fumaric acid or an ester or a salt thereof (e.g., DMF).In some embodiments, the enteric coating on the microspheres isformulated or applied such that the aspirin is released in thegastrointestinal tract (e.g., the small intestine) just prior to (e.g.,1-5, 1-10, 1-15, or 1-20 minutes) the fumaric acid or an ester or a saltthereof (e.g., DMF). Accordingly, in some embodiments, the entericcoating on the aspirin microspheres is thinner than the enteric coatingon the fumaric acid or an ester or a salt thereof (e.g., DMF)microspheres.

It is contemplated that by co-administering the aspirin and fumaric acidor an ester or a salt thereof (e.g., DMF) to the patient in such a waythat the aspirin is absorbed within less than about 5 minutes (or lessthan about 10 minutes, 15 minutes, 20 minutes, 25 minutes or 30 minutes)of, or substantially simultaneously to, the fumaric acid or an ester ora salt thereof (e.g., DMF), the bioavailability of the fumaric acid oran ester or a salt thereof (e.g., DMF) will be enhanced such that thetherapeutically effective dose is about 480 mg/day or less, or at leastabout 360 mg/day, or about 360 mg/day, or about 380 mg/day, or about 400mg/day, or about 410 mg/day, or about 420 mg/day, or between about 360mg/day and 420 mg/day, or between about 360 mg/day and 480 mg/day.

In some embodiments, the microspheres described herein comprise about80% w/w, or about 75% w/w, or about 70% w/w, or about 65% w/w activeingredient (i.e., aspirin or fumaric acid or an ester or a saltthereof).

In one embodiment, an example co-formulation has a chewable outer layeras the dissolvable portion, such that it can be absorbed quickly. Thischewable layer may be adhered directly to the inner layer (theswallowable portion), or it may be such designed that when it is bittenlightly (e.g. with minimal force, such as the force needed to chew abanana), this outer chewable layer breaks off into many pieces withinthe mouth, and can be chewed and thus absorbed, leaving the hard innerlayers in the mouth to be swallowed. By making the chewable layer“crumble” in such a way, the patient will avoid biting hard through thehard inner layer of the tablet, which could be uncomfortable if theinner tablet is very hard, or could damage the integrity of the innertablet, allowing it to be absorbed earlier than desired.

This may be similar to eating a cherry, where one bites the outer layeroff and eats it, but does not bite too hard to chip their tooth on thehard inner pit. However, in the inventive tablet the patient would thenswallow the inner tablet, instead of spitting out the cherry pit.

The outer chewable layer can be formulated, e.g., with a water solublesugar and/or a sugar substitutes. Suitable water-soluble sugars and/orsugar substitutes are glucose, maltose, sucrose, dextrose, fructose,sorbitol, mannitol or other types of natural or artificial sweeteners.Mixtures of various sugars or sugar substitutes are also suitable.

The chewable layer can also be formulated with, e.g., a gel formingagent. Examples of such suitable gel formers are xanthan gum,methylcelluloses such as sodium carboxymethylcellulose orhydroxypropylmethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, alginates, tragacanth or edible starch. Thesesubstances are all commercially available and usually meet the purityrequirements and quality regulations for pharmaceutical products. Allsuch gel formers and coatings contemplated are GRAS (generally regardedas safe).

Wetting agents and lubricants such as sodium lauryl sulfate, as well ascoloring agents, flavoring agents, sweetening agents (including othernonnutritive sweeteners), tableting agents, stabilizers, antioxidants,cooling agents, and preservatives, can also be present.

A binding agent can also be present such as cellulose, cellulosicderivatives, polyvinyl pyrrolidone, starch, modified starch, andmixtures thereof, and, in particular, microcrystalline cellulose.

One example of a manufacturing technique to formulate the chewablecomponent over the solid dosage form is compression coating. Thecompression coating can be prepared by, e.g., a Manesty Dry-Cota press,which consists of two side by side interconnected tablet presses wherethe core is made on one press then mechanically transferred to the nextpress for compression coating. Each “press” has an independent powderfeed mechanism so that core blend is loaded on one machine and coatingblend on the other. Mechanical transfer arms rotate between the machinesto remove cores from one press and transfer them to the coating press.Other and more modern types of presses which may be used (e.g. ElizabethHata HT-AP44-MSU-C, Killian RUD, Fette PT 4090) have a dual feed systemfor coating blend and pre-made cores. This configuration is moreflexible, in that cores can be pan coated with a functional or cosmeticcoating before compression coating. However, any conventional,art-recognized manufacturing technique that permits the formulation of achewable component over a solid dosage form will be readily appreciatedby the skilled artisan and is contemplated by the present disclosure.

A similar embodiment would not only have an outer chewable layer, butalso a thin shell outside of the chewable layer. This would be similarto the thin candy shell of an M&M candy. With this thin outer shellhelping to hold the tablet together, the chewable layer can be designedto more easily crumble and dissolve than if there was no outer shell,e.g., by reducing the amount of binder or by reducing the compression tothat which will minimally hold the chewable component together until theouter shell is applied.

The outer shell can be a sugar coating or a polymer coating such ashydroxypropylmethylcelluose or polyvinylalcohol or combinations thereof,for example.

Another embodiment contemplated by the present disclosure is an outerlayer made from liquid, within a thin outer skin or shell. When thepatient bites lightly on the tablet, this outer skin would fracture,allowing the liquid (or gel) of a fast-absorbing medication to releaseinto the mouth and thus be absorbed quickly, starting at the mouth'smucous membranes. There are several possible embodiments of this outerlayer, including viscous liquids, gels, quick absorbable substances,powder within a breakable skin, substances that “melt” in the mouth(quickly absorb) and more. In another embodiment of this example, theliquid can be comprised of two or more substances and can also includesolid particles which can be comprised of one or more substances. Inthis embodiment, the solid particles would be suspended in the liquid.The solid particles could also dissolve over time into the liquid.

When the outer layer is manufactured to absorb quickly, the drug can beformulated with a water soluble excipient such as a sugar, sugaralcohol, polyethylene glycol (PEG), or polyethylene oxide. The preferredwater-soluble excipients are the sugar alcohols including, but notlimited to sorbitol, mannitol, maltitol, reduced starch saccharide,xylitol, reduced paratinose, erythritol, and combinations thereof. Thepreferred sugar is glucose. Other suitable water-soluble excipientsinclude gelatin, partially hydrolyzed gelatin, hydrolyzed dextran,dextrin, alginate and mixtures thereof. A disintigrating agent such assodium starch “meltable” formulation can be readily determined by one ofskill in the art.

When the outer layer contains a liquid within an outer skin, the outerskin can be gelatin and the drug can be mixed with water or misciblesolvents such as propylene glycol; PEG's and ethanol, or an oleaginousmedium, e.g., peanut oil, liquid paraffin or olive oil.

Another embodiment has an outer layer which rapidly dissolves whensucked on. When the inner layer is reached, the patient would swallowthe tablet. This embodiment can be designed such that the outer surfaceof the inner, hard layer has a texture that is easily recognized by thetongue, so that it is clear to the patient when the outer layer is fullydissolved, and thus when it is time to swallow the inner layer. Thiswould be similar to a Tootsie Pop®, in that the Tootsie Roll® center iseasily recognized by the tongue as feeling very different than the outerdissolvable candy.

In such an embodiment, the dissolvable portion can be formulated in adissolvable matrix material. The dissolvable matrix may includecarbohydrates, fats, proteins, waxes (natural and synthetic),hydrocarbons, and other materials which safely and rapidly dissolve inthe mouth.

The inner, swallowable “slow absorb” or “extended release” layercontemplated by the present disclosure can have any number ofart-recognized constituencies. In one embodiment, the inner layer isdesigned similar to a standard tablet. In another embodiment, the innerlayer is enteric coated, further slowing the release of the medication.In still another embodiment the inner layer can be an extended releasedosage form.

When the inner layer has an enteric coating, the coating can be, e.g., amaterial selected from the group consisting of one or more of thefollowing: cellulose acetate phthalate, alginates, alkali-solubleacrylic resins, hydroxypropyl methylcellulose phthalate,methacrylate-methacrylic acid copolymers, polyvinyl acetate phthalateand styrol maleic acid copolymers. The coating can also be multilayered;i.e. one or more coatings are contemplated to provide extended releasekinetics which permit the inner tablet to release over a period of from15 minutes to 24 hours or more.

The extended release dosage form can be formulated with the drugdispersed in a matrix or with an extended release coating. Suitablematerials form inclusion in an extended release matrix or coating canbe, e.g., a cellulosic material, an acrylic polymer, or a combinationthereof.

The contemplated inner layer can also be made of a substance which issofter and more pliable than a standard hard tablet, e.g. similar to ahard taffy. In this way, the patient could not chip their teeth whenbiting the tablet, as the inner layer will absorb some of the shock ofthe bite without breaking or dissolving. It can then by swallowed to beabsorbed in the GI system, after the outer layer was absorbed in themouth.

The “taffy” can be prepared, e.g., with an admixture of a sugar melthaving at least 40% sugar, such as fructose and a surface active agent.However, the skilled artisan can readily prepare alternativeformulations of sugar-based substances to achieve an inner core thatabsorbs the shock of the chewing force exerted by an individual in thenormal course of taking a chewable medication.

In another example, the dissolvable portion can include two or morediscrete pulverizable portions or layers. All discrete pulverizablelayers will be dispersed in the oral cavity by masticating, therebyreleasing the layers from the hard inner core.

Compounds which may be included in the two or more discrete pulverizableportions or layers include sodium lauryl sulfate, as well as coloringagents, flavoring agents, sweetening agents (including othernonnutritive sweeteners), tableting agents, stabilizers, antioxidants,cooling agents, and preservatives, suitable water-soluble sugars and/orsugar substitutes including glucose, maltose, sucrose, dextrose,fructose, sorbitol, mannitol or other types of natural or artificialsweeteners, gel forming agents including xanthan gum, methylcellulosessuch as sodium carboxymethylcellulose or hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, alginates, tragacanth andsoluble starch, binding agents including cellulose, cellulosicderivatives, polyvinyl pyrrolidone, starch, modified starch, andmicrocrystalline cellulose, water soluble excipients such as a sugar,sugar alcohol, polyethylene glycol (PEG), or polyethylene oxide,sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol,reduced paratinose, erythritol, gelatin, partially hydrolyzed gelatin,hydrolyzed dextran, dextrin, alginate, naproxen sodium (sodium(2S)-2-(6-methoxynaphthalen-2-yl)propanoate) and ibuprofen(2-[4-(2-methylpropyl)phenyl]propanoic acid), aspirin, a COX inhibitor,COX-2 specific inhibitors such as colecoxib (Celebrex™)(4-[5-(4-methylphenyl-3-)trifluoromethyl)pyrazol-1-yl]benzenesulfonamide)and rofecoxib (Vioxx™)(4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one), Percocet™(combination of acetaminophen and oxycodone), Tylenol acetaminophen, anNSAID an anti-emetic, a sedative, an anesthetic, an amnesiatic,acetaminophen, diclofenac, aspirin, laropiprant, or vitamins such asVitamin C, and more, or any combination of the above. These discretelayers may also cover only a portion of the hard inner core, orswallowable portion.

EXAMPLES

The following examples are included to demonstrate specific embodimentsof the disclosure. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques to function well in the practice of the disclosure, and thuscan be considered to constitute specific modes for its practice.However, those of skill in the art should, in light of the presentdisclosure, appreciate that many changes can be made in the specificembodiments which are disclosed and still obtain a like or similarresult without departing from the spirit and scope of the disclosure.

Example 1 Intraoral Administration of Aspirin Reduces Fumarate-InducedFlush More than Swallowed Aspirin

Seven human patients with multiple sclerosis who were already takingdimethyl fumarate and had experienced flushing side effects fromdimethyl fumarate were recruited for this study. Each patient did nothave an allergy or reaction to aspirin or dimethyl fumarate (DMF), hadnot been diagnosed with kidney disease or liver disease, was notpregnant or planning to be pregnant within the following two months, hadnot been breastfeeding within the preceding two months, and had not usedaspirin for the preceding 7 days.

In Period I, each patient was given their standard dose of 240 mgdimethyl fumarate orally. Each patient was asked to rate his or herflush on the Global Flush Severity Scale (GFSS) (see Paolini et al. Int.J. Clin. Pract. 62(6):896-904 (2008)), when the flush completelyresolved. The Global Flushing Severity Score measures, overall, in theprevious 24 hours, how each patient rates the flushing symptoms,including redness, warmth, tingling, and itchiness of the skin.

Period II did not start until at least two days upon completion ofPeriod I. At Period II, each patient orally swallowed 162 mg aspirinfollowed by 240 mg dimethyl fumarate. After the flush completelyresolved, then each patient recorded his or her GFSS flush rating.

Not until at least two days later did Period III start. At Period III,each patient was asked to not swallow the orally administered aspirin(162 mg) but to allow the aspirin to be absorbed through the oralmucosa. The aspirin was in powdered form and the remaining aspirin inthe mouth was washed out with water. Afterwards, 240 mg of dimethylfumarate was swallowed with a glass of water. Still, the flush was rated(GFSS) after it was resolved.

The patients during Period III suffered the least severe flush thanduring any other Periods. Among Periods I through II, the severity offlush was the lowest in Period III (a 52% reduction as compared toPeriod I), second lowest in Period II (a 33% reduction as compared toPeriod I) and the highest in Period I. As the total amount of aspirinwas the same between Period II and III, this example thereforedemonstrates that oral release of aspirin greatly increased aspirin'santi-flushing effect for dimethyl fumarate.

Example 2 Dose Ranging Study

Two hundred and twenty subjects will be recruited for the purposes ofthis trial. Eligible patients must have a diagnosis of release-remittingmultiple sclerosis (RMMS), and at least one relapse in the 12 monthsprior to randomization. The trial is a randomized, double-blind,placebo-controlled, dose-ranging trial in RMMS patients already takingDMF. The trial is scheduled to last 48 weeks. Prior to the 48 weeks ofon-trial time, patients will be randomly assigned, in a 1:1:1:1:1allocation, to one of five treatments: (i) DMF 180 mg/VTS-ASA (aspirin)200 mg twice daily; (ii) DMF 240 mg/VTS-ASA 200 mg twice daily; (iii)DMF 300 mg/VTS-ASA 200 mg twice daily; (iv) DMF 300 mg/VTS-ASA 200 mgonce daily; and (v) Placebo 240 mg twice daily. Both patients andpractitioners were will be blinded to the treatment regime. Studyparticipants will report to the clinical research unit (CRU) every 4weeks during the study period for routine medical monitoring, and every4 weeks for the first 24 weeks for brain MRI scans.

Study participants will be evaluated for the following primaryendpoints; (i) Number of new GdE lesions in weeks 12-14; (ii) Number ofnew GdE lesions in weeks 4-24; (iii) Number of new GdE lesions perpatient in weeks 12-24; (iv) ARR during weeks 0-24; (v) ARR during weeks25-48; (vi) ARR during weeks 0-48. Secondary safety endpoints include;(i) headache; (ii) nasopharyngitis; (iii) nausea; (iv) diarrhea; (v)abdominal pain; (vi) lower limb fracture; (vii) pelvic inflammatorydisease; (viii) phlebitis; (ix) urinary retention; and (x) uterineleiomyoma.

In addition to the primary and secondary endpoints listed above, theproposed trial will additionally investigate endpoints that are specificto the inquiry of the effect of pretreatment of aspirin with DMF. Theseendpoints include; (i) occurrence of flush; (ii) occurrence of pruritus;(iii) occurrence of hot flush; (iv) Global Flushing Severity Score(GFSS); (v) Fatigue Severity Score (FSS); (vi) Number of new orenlarging T2-hyperintense lesions at week 24, a metric of remyelination;(vii) Number of new T1-hypointense lesions at week 24, a metric ofremyelination; and (viii) PHQ-9 Depression Score.

Clinically meaningful differences between treatment groups will beevaluated at the end of the study period according to intention to treat(ITT) principals.

Example 3 Bioequivalence Study

The bioequivalence study will be performed in two parts; a pilot study(about 20 healthy subjects), followed by a Phase 1 study (about 125subjects). The pilot study in healthy males and females is designed toestablish a pharmacokinetic (PK) profile under fasting and fedconditions for the orally administered test and reference products tocompare the bioavailability in accordance with Food and DrugAdministration (FDA) and Center for Drug Evaluation and Research (CDER)guidelines. Phase 1 subjects have a diagnosis of release-remittingmultiple sclerosis (RMMS), and at least one relapse in the 12 monthsprior to randomization.

Subjects in both studies will be randomly assigned, in a 1:1:1:1allocation, to one of four treatments: oral administration of (i)aspirin only (control); (ii) DMF only; (iii) DMF/aspirin combination inthe fasted state; (iv) DMF/aspirin combination in the fed state. Bothpatients and practitioners will be blinded to the treatment regime.

Study Objectives

To investigate the PK profiles of the test product, DMF 180 mg/ASA 150mg capsules and the reference products, DMF 240 mg delayed-releasedcapsules and Bayer Aspirin® 325 mg tablets, and to determine the samplesize for future studies.

For this purpose the PK profiles of DMF's metabolite, monomethylfumarate(MMF), acetylsalicylic acid (ASA) and its active metabolite, salicylicacid (SA) in plasma will be investigated after administration of asingle dose of the test and reference formulations, under fasting andfed conditions.

These will be a single-dose, open-label, laboratory-blind, randomized,four period crossover pilot study with orally administereddimethylfumarate and aspirin conducted under fasting and fed conditions.

The studies will comprise:

-   -   Screening period of maximum 21 days;    -   Four treatment periods (each of which will include a profile        period of 12 hours separated by a wash-out period of 3 calendar        days (minimum number of days based on half-life of the        analyte/metabolites) to 7 calendar days (maximum number of days        based on logistical arrangements) between consecutive        administrations of the IMP, and    -   A post-study visit within 72 hours of completion of the last        treatment period of the study.

Procedures listed for the post-study visit will be performed in theevent of early withdrawal from the study. Subjects will be assignedrandomly to treatment sequence, before the first administration of IMP.

The duration of this study is expected to be approximately 25 days(approximately 3½ weeks) per subject (excluding the screening period).The actual overall study duration and study recruitment time may vary.

Along with other assessments during the screening period and admission,during the treatment period the subjects vital signs will be assessedand they will be assessed for adverse events and concomitant medicationand pharmacokinetic blood samples will be collected at the followingtime points: at pre dose (0 hours), at 15 minutes (acetylsalicylic acidand salicylic acid only), 30 minutes, 45 minutes (acetylsalicylic acidand salicylic acid only) and at 1 hour, 1 hour 30 minutes, 2 hours, 2hours 30 minutes, 3 hours, 3 hours 30 minutes, 4 hours, 5 hours, 6hours, 7 hours, 8 hours, 10 hours and 12 hours post dose (total: 17samples per treatment period). If applicable, the collection of PK bloodsamples take precedence over other assessments at a scheduledtime-point.

Subjects will receive either the test or reference product, according tothe randomization schedule, under fasting and fed conditions. Subjectswill receive each product once.

Treatment A - DMF only fasting (Reference 1) API: Dimethylfumarate (DMF)Dosage form and strength: 240 mg delayed release capsule Study dose: 240mg (1 capsule) Route of administration: Oral

Treatment B - Aspirin only fasting (Reference 2) API: Aspirin(acetylsalicylic acid [ASA]) Dosage form and strength: 325 mg tabletStudy dose: 325 mg (1 tablet) Route of administration: Oral

Treatment C - DMF/aspirin (ASA) fasting (Test 1) API: DMF 180 mg/aspirin(ASA) 150 mg Dosage form and strength: DMF 180 mg/aspirin (ASA) 150 mgfixed dose combination capsule Study dose: DMF 180 mg/aspirin (ASA) 150mg capsule (1 capsule) Route of administration: Oral (the outer layer ofthe fixed dose combination capsule contains aspirin that dissolves inthe mouth before the remaining part of the capsule is then swallowedwhole with water)

Treatment D - DMF/aspirin (ASA) fed (Test 2) API: DMF 180 mg/aspirin(ASA) 150 mg Dosage form and strength: DMF 180 mg/aspirin (ASA) 150 mgfixed dose combination capsule Study dose: DMF 180 mg/aspirin (ASA) 150mg capsule (1 capsule) Route of administration: Oral (the outer layer ofthe fixed dose combination capsule contains aspirin that dissolves inthe mouth before the remaining part of the capsule is then swallowedwhole with water)

For the fasting treatment periods, after an overnight fast of at least10 hours, subjects will receive either the reference or the test product(according to the randomization schedule) with 240 mL water. Thereference products must be swallowed whole with water. The fixed dosecombination capsule) must be kept in the mouth until the outer layer(containing the aspirin) has dissolved in the mouth before the capsuleis then swallowed whole with water. Specific details on theadministration of the test product will be provided in a separatedocument, if needed.

For fed treatment period, after an overnight fast of at least 10 hours,subjects will receive a standardized high-fat, high-calorie breakfast 30minutes before administration of IMP. The entire meal must be consumedwithin 30 minutes. After completion of the breakfast subjects willreceive either the reference or the test product (according to therandomization schedule) with 240 mL water. The reference products mustbe swallowed whole with water. The fixed dose combination capsule) mustbe kept in the mouth until the outer layer (containing the aspirin) hasdissolved in the mouth before the capsule is then swallowed whole withwater.

Quantitative analysis of monomethylfumarate, acetylsalicylic acid andsalicylic acid in the collected plasma samples will be performed by BASDusing liquid chromatography with tandem mass spectrometry (LC-MS/MS).

Calculation of the PK parameters will be made with Phoenix® WinNonlin®6.2 (or higher) (Certara, L. P., 1699 South Hanley Road, St Louis, Ms.63144, USA). The PK parameters will be calculated for each subject andtreatment using non-compartmental analysis and using the actual samplingtime intervals (relative to IMP administration).

Primary Pharmacokinetic Parameters for monomethylfumarate,acetylsalicylic acid and salicylic acid:

-   -   Maximum observed plasma concentration (C_(max))    -   Area under the plasma concentration versus time curve, from time        zero to t, where t is the time of the last quantifiable        concentration (AUC(_(0-t)))    -   Area under the plasma concentration versus time curve, with        extrapolation to infinity (AUC(_(0-∞)))

Secondary Pharmacokinetic Parameters for monomethylfumarate,acetylsalicylic acid and salicylic acid

-   -   Time to maximum observed plasma concentration (t_(max))    -   Terminal elimination rate constant (λ_(z))    -   Apparent terminal elimination half-life (t_(1/2·z))

It is contemplated that this study will show that that byco-administering DMF with aspirin as described herein, thebioavailability of the DMF will be increased such that the effectivedose of DMF can be reduced to as low as about 360 mg/day, or 480 mg/dayor less, or about 400 mg/day, about 420 mg/day, or from about 360 mg/dayto about 420 mg/day.

Example 4 Pilot, Randomized, Open-Label, 2-Way Crossover ComparativeBioavailability Study of Dimethyl Fumarate-Acetylsalicylic Acid 180mg-150 mg Delayed-Release Capsule (vts-72) and Tecfidera 240 mgDelayed-Release Capsule (reference) following a Single Dose in HealthySubjects Under Fasting Conditions

The objective of this example was to compare the rate and extent ofabsorption of monomethyl fumarate from a dimethylfumarate-acetylsalicylic acid 180 mg-150 mg delayed-release capsule(VTS-72) (Test; Treatment A) versus Tecfidera 240 mg delayed-releasecapsule (Reference; Treatment B), administered as 1×180 mg-150 mg or1×240 mg delayed-release capsule under fasting conditions.

This was a single center, pilot, comparative bioavailability,open-label, randomized, single-dose, 2-period, 2-sequence, crossoverstudy under fasting conditions. A total of 12 healthy adult male orfemale volunteers were included in this pilot study. For each period,subjects will be confined from at least 10 hours before dosing until 12hours post-dose. There were a washout of 7 days or more between doses.The washout period could be increased for logistical considerations.Participation of each subject in this study lasted approximately 9 days.Subjects were administered each treatment according to the 2-period,2-sequence, block randomization scheme.

Treatment A: Subjects were required not to wear dentures or to removetheir tongue piercing at the time of dosing. The delayed-release capsulewere placed on the subject's tongue. Subjects were instructed to suckthe delayed-release capsule until the acetylsalicylic acid coating wasdissolved or up to a maximum of 1 minute after the delayed-releasecapsule had been placed on the subject's tongue. The delayed-releasecapsule should not be chewed, bitten, or swallowed during that 1 minuteperiod or until the coating is dissolved; only the saliva could beswallowed. The subject was instructed to give a hand sign once theacetylsalicylic acid coating was dissolved (the capsule should feel andtaste different). Thereafter, or up to a maximum of 1 minute after thedelayed-release capsule was placed on the subject's tongue, 240 mL ofwater was given to subjects to swallow the capsule. Time of dosing wasset to the time the capsule was placed on the tongue. A hand and mouthcheck was performed to ensure consumption of the medication.

Treatment B: Study medication was administered to each subject and wasswallowed whole with 240 mL of water without being sucked, chewed orbitten, and a hand and mouth check was performed to ensure consumptionof the medication.

Flushing (including redness, warmth, tingling, and itchiness of theskin) was assessed at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, and 4 hours post-doseusing the question and the rating scale presented in Section-FlushingAssessment below. Half grades were not assigned. Flushing symptoms wererecorded as adverse events.

GI symptoms were assessed at 10 hours post-dose using the questions andthe rating scale presented in Section-Gastrointestinal SymptomsAssessment below. Half grades were not assigned. GI symptoms wererecorded as adverse events.

Flushing Assessment

Flushing was assessed using the question below. The question was askedby the clinical staff:

-   -   Question 1: Overall, at this moment, how would you rate your        flushing symptoms (including redness, warmth, tingling, and        itchiness of the skin)? Score from 0 to 10 (none 0, mild 1 to 3,        moderate 4 to 6, severe 7 to 9, extreme 10).

FIG. 1 is an example of the scale that was used to rate the assessmentof Question 1.

Gastrointestinal Symptoms Assessment

Gastrointestinal symptoms were assessed using the questions below.Questions were asked by the clinical staff:

-   -   Question 2: Overall, during the past 10 hours, how would you        rate your GI side effects (nausea, diarrhea, upper abdominal        pain, lower abdominal pain, vomiting, indigestion, constipation,        bloating, and flatulence)?    -   Question 3: Overall, during the past 10 hours, how bothersome        were your GI side effects (nausea, diarrhea, upper abdominal        pain, lower abdominal pain, vomiting, indigestion, constipation,        bloating, and flatulence)?

FIG. 2 is an example of the scale that was used to rate the assessmentof Questions 2 and 3.

The flushing side effect reported by each of the subject is summarizedin Table 1 below. The total reduction of flushing from 15.9 to 7.9 wasabout 50.3%. When the doses of DMF were normalized to 180 mg in bothtreatments, the reduction was still 33.6%. Considering that, as shownbelow, aspirin increased the bioavailability of DMF by about 5%, thereduction of the flushing side effect is actually about 36.8%. Alsointerestingly, 6 of these 11 subjects had their flushes peak at least 30mins earlier with VTS-72 (only 2 were later) than with DMF alone.

TABLE 1 Summary of Flush Ratings Total Flush Rating* Treatment ATreatment B (180 mg DMF + 150 mg Subject # (240 mg DMF) Aspirin) 1 (dropout) (drop out) 2 26 5 3 8 8 4 18 14 5 26 13 6 14 6 7 36 13 8 8 2 9 11 910 9 0 11 8 15 12 11 2 Mean 15.9 7.9 Normalized 11.9 7.9 Mean *Flusheswere scored from 0-10 every 30 mins, up to 4 hours post dose (8 totalmeasurements per dose) and added up

Table 2 below provides a descriptive statistics summary of monomethylfumarate plasma pharmacokinetic parameters.

TABLE 2 Descriptive Statistics Summary of Monomethyl Fumarate PlasmaPharmacokinetic Parameters Treatment A Treatment B Parameter (units) NMean SD CV % N Mean SD CV % AUC_(0-t) (h*ng/mL) 11 3874.01 1213.13 31.3111 4924.24 1550.02 31.48 AUC_(0-inf) (h*ng/mL) 11 3885.63 1214.97 31.2711 4958.99 1544.26 31.14 Residual area (%) 11 0.32 0.16 49.93 11 0.741.79 243.23 C_(max) (ng/mL) 11 2034.02 599.26 29.46 11 2749.40 988.7935.96 T_(1/2 el) (h) 11 0.62 0.14 22.14 11 0.75 0.27 35.53 K_(el) (/h)11 1.1618 0.2268 19.5244 11 1.0149 0.2926 28.8326 Correlation 11 −0.99780.0023 −0.2328 11 −0.9639 0.0689 −7.1439 K_(el Lower) (h) 11 4.768 0.95920.105 11 5.364 1.002 18.687 K_(el Upper) (h) 11 7.269 1.349 18.553 118.360 1.362 16.287

When the mean values in both treatments were normalized to 180 mg DMF,the mean values are summarized in Table 3. Co-administration of aspirindid not have significant impact on the C_(max) of DMF. However, theco-administration of aspirin caused an about 5% increase in AUC_(0-t)and AUC_(0-inf). Also surprisingly, the data showed very tightinter-subject variability (confidence intervals).

TABLE 3 Statistics Summary after Dose Normalization Treatment B Change %Treatment A (normalized) (A over B) AUC_(0-t) (h*ng/mL) 3874.01 3693.184.90% AUC_(0-inf) (h*ng/mL) 3885.63 3719.2425 4.47% Residual area (%)0.32 0.555 −4.23% C_(max) (ng/mL) 2034.02 2062.05 −1.36%

Also interestingly, even though the C_(max) did not have a significantchange, the co-administration of aspirin shifted the T_(max) to about 20minutes earlier (median). See Table 4.

TABLE 4 Summary Statistics of T_(max) Parameter Treatment A Treatment B(units) N Median Min Max N Median Min Max T_(max) (h) 11 2.330 1.3274.499 11 2.661 0.747 4.994

This example demonstrates that co-administration of aspirin increasedthe bioavailability of DMF by about 5% while at the same time reducingthe flushing side effect by more than 35%.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs.

The disclosures illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising”, “including,” “containing”, etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the disclosure claimed.

Thus, it should be understood that although the present disclosure hasbeen specifically disclosed by preferred embodiments and optionalfeatures, modification, improvement and variation of the disclosuresembodied therein herein disclosed may be resorted to by those skilled inthe art, and that such modifications, improvements and variations areconsidered to be within the scope of this disclosure. The materials,methods, and examples provided here are representative of preferredembodiments, are exemplary, and are not intended as limitations on thescope of the disclosure.

The disclosure has been described broadly and generically herein. Eachof the narrower species and subgeneric groupings falling within thegeneric disclosure also form part of the disclosure. This includes thegeneric description of the disclosure with a proviso or negativelimitation removing any subject matter from the genus, regardless ofwhether or not the excised material is specifically recited herein.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

All publications, patent applications, patents, and other referencesmentioned herein are expressly incorporated by reference in theirentirety, to the same extent as if each were incorporated by referenceindividually. In case of conflict, the present specification, includingdefinitions, will control.

It is to be understood that while the disclosure has been described inconjunction with the above embodiments, that the foregoing descriptionand examples are intended to illustrate and not limit the scope of thedisclosure. Other aspects, advantages and modifications within the scopeof the disclosure will be apparent to those skilled in the art to whichthe disclosure pertains.

What is claimed is:
 1. A dosage form comprising an effective amount ofaspirin and an effective amount of fumaric acid or an ester or a saltthereof, wherein the aspirin and fumaric acid or an ester or a saltthereof are each individually formulated as enterically coatedmicrospheres.
 2. The dosage form of claim 1, wherein the entericallycoated microspheres are formulated such that the aspirin and fumaricacid or an ester or a salt thereof are released in the gastrointestinaltract at substantially the same time.
 3. The dosage form of claim 1,wherein the enterically coated microspheres comprising aspirin areformulated such that the aspirin is released in the gastrointestinaltract within about one to 20 minutes prior to the fumaric acid or anester or a salt thereof is released in the gastrointestinal tract. 4.The dosage form of claim 1, wherein the fumaric acid or an ester or asalt thereof is dimethyl fumarate.
 5. The dosage form of claim 1,wherein the dosage form consists essentially of an effective amount ofaspirin and an effective amount of dimethyl fumarate.
 6. The dosage formof claim 1, comprising from about 80 mg to about 450 mg of dimethylfumarate.
 7. The dosage form of claim 1, wherein the enterically coatedmicrospheres comprising aspirin comprise from about 20 mg to about 500mg of aspirin.
 8. An enteric coated capsule comprising the dosage formof claim
 1. 9. The capsule of claim 8, wherein the capsule is furthercoated with a second dose of aspirin formulated to dissolve in an oralcavity of a subject.
 10. The capsule of claim 9, wherein the second doseof aspirin is from about 20 mg to about 500 mg.
 11. A capsule comprisinga dosage form comprising an effective amount of aspirin and an effectiveamount of fumaric acid or an ester or a salt thereof, wherein theaspirin and fumaric acid or an ester or a salt thereof are eachindividually formulated as enterically coated microspheres containedwithin the capsule shell.
 12. The capsule of claim 11, wherein thecapsule is coated with a second dose of aspirin formulated to dissolvein an oral cavity of a subject.
 13. The capsule of claim 12, comprisingfrom about 20 mg to about 500 mg of aspirin.
 14. The dosage form ofclaim 1, which comprises 75 mg to 325 mg aspirin and 150 mg to 225 mg ofthe fumaric acid or an ester or a salt thereof.
 15. The dosage form ofclaim 1, which comprises 75 mg to 325 mg aspirin and 150 mg to 225 mg ofdimethyl fumarate.
 16. The dosage form of claim 15, further comprising aportion of aspirin which is formulated to dissolve in an oral cavity ofa subject.
 17. The dosage form of claim 1, which comprises 150 mg to 650mg aspirin and 300 mg to 450 mg of dimethyl fumarate.
 18. The dosageform of claim 17, further comprising a portion of aspirin which isformulated to dissolve in an oral cavity of a subject.